Hao Huang Hao Huang Iva Splichalova Iva Splichalova Nelli Blank-Stein Nelli Blank-Stein Maria Francesca Viola Maria Francesca Viola Eliana Franco Taveras Eliana Franco Taveras Kerim Acil Kerim Acil Diana Fink Diana Fink Franzisca Petrovic Franzisca Petrovic Nikola Makdissi Nikola Makdissi Seyhmus Bayar Seyhmus Bayar Katharina Mauel Katharina Mauel Carolin Radwaniak Carolin Radwaniak Jelena Zurkovic Jelena Zurkovic Amir H. Kayvanjoo Amir H. Kayvanjoo Klaus Wunderling Klaus Wunderling Malin Jessen Malin Jessen Mohamed H. Yaghmour Mohamed H. Yaghmour Lukas Kenner Lukas Kenner Thomas Ulas Thomas Ulas Stephan Grein Stephan Grein Joachim L. Schultze Joachim L. Schultze Charlotte L. Scott Charlotte L. Scott Martin Guilliams Martin Guilliams Zhaoyuan Liu Zhaoyuan Liu Florent Ginhoux Florent Ginhoux Marc D. Beyer Marc D. Beyer Christoph Thiele Christoph Thiele Felix Meissner Felix Meissner Jan Hasenauer Jan Hasenauer Dagmar Wachten Dagmar Wachten Elvira Mass Elvira Mass Nora R. Balzer Nora R. Balzer Lea Seep Lea Seep Springer 2025 Kupffer cells (KCs) are tissue-resident macrophages that colonize the liver early during embryogenesis1. Upon liver colonization, KCs rapidly acquire a tissue-specific transcriptional signature, mature alongside the developing liver and adapt to its functions. Throughout development and adulthood, KCs perform distinct core functions that are essential for liver and organismal homeostasis, including supporting fetal erythropoiesis, postnatal erythrocyte recycling and liver metabolism. However, whether perturbations of macrophage core functions during development contribute to or cause disease at postnatal stages is poorly understood. Here, we utilize a mouse model of maternal obesity to perturb KC functions during gestation. We show that offspring exposed to maternal obesity develop fatty liver disease, driven by aberrant developmental programming of KCs that persists into adulthood. Programmed KCs promote lipid uptake by hepatocytes through apolipoprotein secretion. KC depletion in neonate mice born to obese mothers, followed by replenishment with naive monocytes, rescues fatty liver disease. Furthermore, genetic ablation of the gene encoding hypoxia-inducible factor-α (HIF1α) in macrophages during gestation prevents the metabolic programming of KCs from oxidative phosphorylation to glycolysis, thereby averting the development of fatty liver disease. These results establish developmental perturbation of KC functions as a causal factor in fatty liver disease in adulthood and position fetal-derived macrophages as critical intergenerational messengers within the concept of developmental origins of health and diseases. PDFDocument eng 2026-02-12T08:53:10.838392Z 2025 Haematopoiesis Innate immunity 33676060 b application/pdf http://creativecommons.org/licenses/by-nc-nd/4.0/